In a collaborative study, we characterized a pathway for the synthesis of ceramides with very long chain fatty acids (VLCFA).[unreadable] VLCFA are found as components of glycerolipids and sphingolipids. Elongation of very long chain fatty acids-4 (ELOVL4) gene belongs to a family of 6 members of putative fatty acid elongases that are involved in the formation of VLCFA. Elovl4-/- mice died within several hours of birth. To study functions of ELOVL4 further, we have explored the causes for the postnatal lethality in Elovl4-/- mice. Our data indicated that the mutant mice exhibited reduced thickness of the dermis, delayed differentiation of keratinocytes, and abnormal structure of the stratum corneum. All Elovl4-/- mice exhibited defective skin water permeability barrier function, leading to the early postnatal death. We further showed that the absence of ELOVL4 results in depletion in the epidermis of ceramides with omega-hydroxy very long chain fatty acids (> or = C28) and accumulation of ceramides with non omega-hydroxy fatty acids of C26, implicating C26 fatty acids as possible substrates of ELOVL4. These data demonstrate that ELOVL4 is required for VLCFA synthesis that is essential for water permeability barrier function of skin